Hypertension is a condition characterized by persistent high arterial blood pressure (BP). Hypertension may have no known cause (essential or idiopathic hypertension) or may be associated with other primary diseases (secondary hypertension), and is considered a risk factor for the development of heart disease, peripheral vascular disease, stroke, and kidney disease.
Preeclampsia is a rapidly progressive condition occurring during pregnancy characterized by high BP, edema, and protein in the urine. Preeclampsia is the presence of pregnancy-induced hypertension, accompanied by proteinuria, edema or both, after 20 weeks of fetal gestation. Preeclampsia occurs in 5 to 10 percent of all pregnancies and is most common in first-time pregnancies. Complications of preeclampsia include eclampsia, characterized by convulsions and coma, and intrauterine fetal demise. While the cause(s) of preeclampsia and eclampsia are not fully elucidated, several theories have been put forth. One theory proposes that elevated serum levels of digitalis-like sodium pump ligands (SPLs), which act as Na+/K+-ATPase enzyme inhibitors, play a central role in the increased peripheral vasoconstriction exhibited in preeclampsia. This is thought to be mediated through ion exchange pumps resulting in increased intracellular calcium, which promotes vasoconstriction and resultant hypertension (Hamlyn et al., Fed. Proc. 44:2782-88, 1985).
Chronic renal failure is complicated by the propensity of subjects to develop cardiovascular diseases such as hypertension and uremic cardiomyopathy. Cardiac disease is directly responsible for much of the morbidity and mortality seen in patients with end-stage renal disease (Sartank et al., Circulation 108:2154-2169, 2003). Cardiomyopathy is a disorder of the heart muscle that often leads to myocardial dysfunction, such as hypertrophy, diminished contractility, and reduced pump function. Uremic cardiomyopathy is characterized by a systemic oxidant stress state, marked cardiac hypertrophy, and diastolic dysfunction. Even mild degrees of chronic renal failure confer a significant increase in cardiovascular disease (Garg et al., Kidney Int. 61:1486-1494, 2002). Cardiac myocytes isolated from rats subjected to partial (ie, five-sixth) nephrectomy have diastolic dysfunction in vitro, which can be attributed to reduced sarcoplasmic reticulum calcium ATPase (SERCA) activity and, in turn, appears to be dependent on proportional decreases in SERCA2a protein and mRNA (Kennedy et al., J. Am. Soc. Nephrol. 14:90-97, 2003). Steroid molecules, which bind to the plasmalemmal Na+/K+-ATPase and have structural similarity to the digitalis-like sodium pump ligands (SPLs), accumulate in renal failure.
Bufadienolides, which were discovered in amphibians, inhibit Na+/K+-ATPase activity and cross-react with digitalis antibodies (Flier et al., Science 208:503-05, 1980). Several bufadienolides have been suggested as candidate SPLs in mammals, including MBG, which acts in vitro as a vasoconstrictor (Fedorova et al., Am. J. Hypertens. 10:929-35, 1997 and Lopatin et al., J. Hypertens. 17:1179-87, 1999). Marinobufagenin immunoreactive material purified from human urine is identical to MBG from the toad, Bufo marinus. Enhanced MBG production occurs in pathological states associated with fluid retention, including essential and salt-sensitive hypertension, preeclampsia and uremic cardiomyopathy (Gonick et al, Clin. Exp. Hypertens. 1998; 20: 617-627, Bagrov et al., Hypertension 31:1097-1103, 1998; Fedorova et al., Hypertension 37:462-66, 2001; and Lopatin et al., J. Hypertens. 17:1179-87, 1999, Fedorova et al, Circulation 2002; 105: 1122-1127, Kennedy et al., Hypertension 47:448-495, 2006).